Mitochondria play a crucial role in numerous essential intracellular processes such as intracellular energetic metabolism, particular substance (e.g., fatty acids, etc.) metabolism, etc. Especially, mitochondria are directly involved in the formation and use of free radicals (FR) and reactive oxygen species (ROS). Due to such characteristics, in relation to extreme reactive moieties which may influence many intracellular processes in a living cell, mitochondria has been reported to play a crucial role in programmed cell death.
ROS is produced by a redox reaction in various organisms and can induce deterioration of edible oil and fat or oxidative damage on several biological substances (e.g., lipids, proteins, nucleic acids, and carbohydrates), consequently leading to cell damages through a number of steps (Yen G C. et al., J. Agric. Food Chem., 43, pp 27-32, 1995). An unsaturated fatty acid, which is a component of phospholipid membranes, initiates peroxidation by FR such as ROS in a chain reaction. Therefore, peroxidation by FR leads to overall cytotoxicity as well as increasing permeability of cell membranes, thus being involved in carcinogenesis by inducing aging and pathology of several aging-associated diseases. Radical activity greatly influences progression of various chronic diseases associated with oxidative stress such as atopic diseases, cancer, hypertension, myocardial infarction, arteriosclerosis, rheumatism, cataracts, Parkinson's disease, etc., (De Souza L C. et al., Bioorg. Med. Chem. Lett., 14, pp 5859-5861, 2004), and can act as a factor for weakening immune functions (Pike J. et al., Int. J. Vitam. Nutr. Res., 65, pp 117-120, 1995). Especially, oxidative stress induced by hypergenesis of ROS serves as a cause of many degenerative diseases including neurodegenerative disorders. Mitochondria are where ROS is mainly generated and are intracellular organelles most susceptible to damages by ROS. Therefore, a number of diseases in association with FR and ROS hypergenesis are known to be related to dysfunction of mitochondria.
Thus, for the purpose of recovering mitochondrial functions, carriers and/or drugs targeting mitochondria have been proposed. By repeatedly accumulating a substance in a target compartment of a cell, such approach can allow reaching an effective concentration of the substance. Thus, it has advantages of increased application efficiencies, reduced overall dosages, and reduced possibilities and intensities of side effects.
Currently, a very limited number of mitochondria-targeting biological active substances are known. Examples thereof are mitovitamin E (MitoVitE) or superoxide dismutase and glutathione peroxidase mimetics associated with triphenyl phosphonium, which are disclosed in European Patent 1 534 720.